US2023339922A1PendingUtilityA1
Covalent egfr inhibitors and methods of use thereof
Assignee: DANA FARBER CANCER INST INCPriority: Oct 12, 2020Filed: Mar 28, 2023Published: Oct 26, 2023
Est. expiryOct 12, 2040(~14.2 yrs left)· nominal 20-yr term from priority
C07D 409/14A61P 35/00C07D 235/30C07D 401/04C07D 401/14C07D 403/04C07D 403/14C07D 409/12C07D 413/14C07D 495/04C07D 417/14C07D 487/04C07D 471/04
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Claims
Abstract
The disclosure relates to compounds that act as covalent inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof; wherein:
A is selected from the group consisting of C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered fused bicyclic ring, C 3 -C 10 cycloalkenyl, and 3-10 membered heterocycloalkenyl;
Y is selected from the group consisting of absent, CH, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, and NH;
X is selected from the group consisting of absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3 -C 10 cycloalkenyl, and 3-10 membered heterocycloalkenyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are each optionally substituted with one, two, or three R 5 ;
R 1 is selected from the group consisting of H, halo, CN, OH, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-N(R 7 ) 2 , C 1 -C 6 alkyl-OH, N(R 7 ) 2 , NHC(O)R 7 , C(O)N(R 7 )2, NHC(O)N(R 7 ) 2 , SO 2 N(R 7 ) 2 , OC(O)N(R 7 ) 2 , NHC(O)OR 7 , C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3 -C 10 cycloalkenyl, and 4-10 membered heterocycloalkenyl;
R 4 is selected from the group consisting of H, halo, OH, CN, NO 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl-N(R 7 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)-C 1 -C 6 alkyl, C(O)NH 2 , C(O)NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, P(O)(C 1 -C 6 alkyl) 2 , C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, and 3-10 membered heterocycloalkyl; wherein C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, and 3-10 membered heterocycloalkyl are each optionally substituted with one or two R 6 ;
each R 5 is independently selected from the group consisting of C 1 -C 6 alkyl, OH, CN, NO 2 , C 1 -C 6 haloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl-N(R 7 ) 2 , C(O)-C 1 -C 6 alkyl, C(O)NH 2 , C(O)NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, P(O)(C 1 -C 6 alkyl) 2 , C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, and 3-10 membered heterocycloalkyl;
each R 2 and R 3 is independently selected from the group consisting of:
L 3 is a bond, —NH—, -N(C 1 -C 4 alkyl)-, or C 1 -C 4 alkylene, optionally wherein one or more carbon is independently replaced with —C(O)—, —O—, —S—, -NR L3a -, -NR L3a C(O)-, -C(O)NR L3a -, SC(O)—,C(O)S—, —OC(O)—, —C(O)O—, -NR L3a C(S)—, —C(S)NR L3a —, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, —CsC—, —S(O)—, —S(O)O—, —OS(O)—, -S(O)NR L3a -, -NR L3q S(O)-, —S(O) 2 —, —S(O) 2 O—, —OS(O) 2 —, -S(O) 2 NR L3a -, or -NR L3a S(O) 2 -;
R L3a is hydrogen, C 1 -C 6 alkyl optionally substituted with R 9 , or a nitrogen protecting group;
R L3b is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, and 5-8 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;
or, alternatively, two R L3b groups, together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R 9 ;
each of R E1 , R E2 , R E3 , and R E4 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN, CH 2 OR EE , CH 2 N(R EE ) 2 , CH 2 SR EE , OR EE , N(R EE ) 2 , SR EE , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;
or, alternatively, R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form 3-8 membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R 9 ;
each R EE is independently selected from the group consisting of hydrogen, SO 2 -6-10 membered aryl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;
or, alternatively, two R EE groups, together with the atom to which they are attached, form 4-7 membered heterocycloalkyl;
each Y is independently O, S, CH 2 , or NR E7 ;
R E7 is hydrogen, C 1 -C 6 alkyl, CN, or a nitrogen protecting group;
each R 9 is independently selected from the group consisting of halo, OH, NH 2 , NH(C 1 -C 6 alkyl), and N(C 1 -C 6 alkyl) 2 ;
a is 0, 1, or 2; and
z is 1, 2, or 3;
alternatively, R 3 is
wherein n is 0, 1, 2, 3, 4, or 5.
2 . The compound of claim 1 , wherein:
A is selected from the group consisting of phenyl, 5-10 membered heteroaryl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, and 5-9 membered fused bicyclic ring; X is selected from the group consisting of C 1 -C 3 alkyl, phenyl, and 4-8 membered heterocycloalkyl; R 1 is selected from the group consisting of H, C 1 -C 3 alkyl, halo, and 5-6 membered heteroaryl; R 4 is selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 2 is selected from the group consisting of
R 3 is
.
3 . (canceled)
4 . The compound of claim 1 , wherein A is selected from the group consisting of phenyl, piperidine, thiophene, pyrrolidine, isoxazole, pyrrole, pyridine, isothiazole, pyrazole, imidazole, thiazole, indoline, indolizine, isoindoline, pyrrolopyrazine, and oxazole.
5 - 11 . (canceled)
12 . The compound of claim 1 , wherein X is selected from the group consisting of C 1 -C 4 alkyl, phenyl, azepane, and piperidine.
13 . The compound of claim 1 , wherein R 1 is selected from the group consisting of H, halo, C 1 -C 3 alkyl, and 5-6 membered heteroaryl.
14 . The compound of claim 1 , wherein R 4 is selected from the group consisting of H, halo, and C 1 -C 3 alkyl.
15 . (canceled)
16 . The compound of claim 1 , wherein R 2 is independently selected from the group consisting of:
; and
R 3 is independently selected from the group consisting of:
and
wherein n is 1, 2, 3, or 4.
17 - 18 . (canceled)
19 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 19 , wherein
A is phenyl, 5-9 membered heteroaryl, C 3 -C 6 cycloalkyl, 4-9 membered heterocycloalkyl, and 5-9 membered fused bicyclic ring; R 1 is selected from the group consisting of H, C 1 -C 3 alkyl, halo, and 5-6 membered heteroaryl; R 4 is selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 2 is selected from the group consisting of
R 3 is
wherein each L 3 is independently a bond, —NH—, or -N(C 1 -C 4 alkyl)-; each of R E1 , R E2 , R E3 , and R E4 is independently selected from the group consisting of hydrogen, halogen, N(R EE ) 2 , and C 1 -C 6 alkyl; each Y is independently O, CH 2 , or NR E7 ; R E7 is CN; each R EE is independently hydrogen or SO 2 -6-10 membered aryl optionally substituted with one, two, or three R 9 ; R 9 is halo; a is 1 or 2; and z is 1 or 2.
21 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula III:
or a pharmaceutically acceptable salt thereof;
or a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.
22 . (canceled)
23 . The compound of claim 21 , wherein
X is selected from the group consisting of C 1 -C 3 alkyl, phenyl, and 4-8 membered heterocycloalkyl; R 1 is selected from the group consisting of H, C 1 -C 3 alkyl, halo, and 5-6 membered heteroaryl; R 4 is selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 2 is selected from the group consisting of
R 3 is
wherein each L 3 is independently a bond, —NH—, -N(C 1 -C 4 alkyl)-; each of R E1 , R E2 , R E3 , and R E4 is independently selected from the group consisting of hydrogen, halogen, N(R EE ) 2 , and C 1 -C 6 alkyl; each Y is independently O, CH 2 , or NR E7 ; R E7 is CN; each R EE is independently hydrogen or SO 2 -6-10 membered aryl optionally substituted with one, two, or three R 9 ; R 9 is halo; a is 1 or 2; and z is 1 or 2.
24 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula V:
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 24 , wherein
X is selected from the group consisting of C 1 -C 3 alkyl, phenyl, and 4-8 membered heterocycloalkyl; R 1 is selected from the group consisting of H, C 1 -C 3 alkyl, halo, and 5-6 membered heteroaryl; R 4 is selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 2 is selected from the group consisting of
R 3 is
wherein each L 3 is independently a bond, —NH—, -N(C 1 -C 4 alkyl)-; each of R E1 , R E2 , and R E3 is independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl; each Y is independently O or CH 2 ; and a is 1 or 2.
26 . The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
27 - 29 . (canceled)
30 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
31 . A method of inhibiting the activity of EGFR in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
32 . A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
33 . The method of claim 32 , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.
34 . The method according to claim 32 , wherein the cancer is non-small cell lung cancer (NSCLC).
35 . A method of inhibiting the activity of EGFR in a subject in need thereof comprising targeting both Cys775 and Cys797 on EGFR.
36 . The method of claim 35 , wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof; wherein:
A is selected from the group consisting of C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered fused bicyclic ring, C 3 -C 10 cycloalkenyl, and 3-10 membered heterocycloalkenyl;
Y is selected from the group consisting of absent, CH, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, and NH;
X is selected from the group consisting of absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3 -C 10 cycloalkenyl, and 3-10 membered heterocycloalkenyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are each optionally substituted with one, two, or three R 5 ;
R 1 is selected from the group consisting of H, halo, CN, OH, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-N(R 7 ) 2 , C 1 -C 6 alkyl-OH, N(R 7 ) 2 , NHC(O)R 7 , C(O)N(R 7 )2, NHC(O)N(R 7 ) 2 , SO 2 N(R 7 ) 2 , OC(O)N(R 7 ) 2 , NHC(O)OR 7 , C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3 -C 10 cycloalkenyl, and 4-10 membered heterocycloalkenyl;
R 4 is selected from the group consisting of H, halo, OH, CN, NO 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)-C 1 -C 6 alkyl, C(O)NH 2 , C(O)NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, P(O)(C 1 -C 6 alkyl) 2 , C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, and 3-10 membered heterocycloalkyl; wherein C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, and 3-10 membered heterocycloalkyl are each optionally substituted with one or two R 6
each R 5 is independently selected from the group consisting of C 1 -C 6 alkyl, OH, CN, NO 2 , C 1 -C 6 haloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C(O)-C 1 -C 6 alkyl, C(O)NH 2 , C(O)NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, P(O)(C 1 -C 6 alkyl) 2 , C 6 -C 1O aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, and 3-10 membered heterocycloalkyl;
each R 2 and R 3 is independently selected from the group consisting of:
L 3 is a bond, —NH—, -N(C 1 -C 4 alkyl)-, or C 1 -C 4 alkylene, optionally wherein one or more carbon is independently replaced with —C(O)—, —O—, —S—, -NR L3a -, -NR L3a C(O)-, -C(O)NR L3a -, SC(O)—,C(O)S—, —OC(O)—, —C(O)O—, -NR L3a C(S)—, —C(S)NR L3a —, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, —C≡C—, —S(O)—, —S(O)O—, —OS(O)—, -S(O)NR L3a -, -NR L3a S(O)-, —S(O) 2 —, —S(O) 2 O—, —OS(O) 2 —, -S(O) 2 NR L3a -, or -NR L3a S(O) 2 -;
R L3a is hydrogen, C 1 -C 6 alkyl optionally substituted with R 9 , or a nitrogen protecting group;
R L3b is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, and 5-8 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;
or, alternatively, two R L3b groups, together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R 9 ;
L 4 is a bond or C 1 -C 6 alkyl optionally substituted with one, two, or three R 9 ;
each of R E1 , R E2 , R E3 , and R E4 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN, CH 2 OR EE , CH 2 N(R EE ) 2 , CH 2 SR EE , OR EE , N(R EE ) 2 , SR EE , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;
or, alternatively, R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form 3-8 membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R 9 ;
each R EE is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;
or, alternatively, two R EE groups, together with the atom to which they are attached, form 4-7 membered heterocycloalkyl;
R E6 is hydrogen, C 1 -C 6 alkyl, or a nitrogen protecting group;
each Y is independently O, S, CH 2 , or NR E7 ;
R E7 is hydrogen, C 1 -C 6 alkyl, or a nitrogen protecting group;
each R 9 is independently selected from the group consisting of halo, OH, NH 2 , NH(C 1 -C 6 alkyl), and N(C 1 -C 6 alkyl) 2 ;
a is 0, 1, or 2; and
z is 1, 2, or 3;
alternatively, R 3 is
wherein n is 0, 1, 2, 3, 4, or 5.Join the waitlist — get patent alerts
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